TW210338B - - Google Patents

Description

si. 11.19 ^ Ministry of Central Standard 印 印 4 ^ 1〇4Ϊ9 ("Amended Page of Patent Application No. 90 ^ November, 1981, Amendment V. Description of the invention (this invention is about formula C)) Things 〇

R '

R R R R where «· R1 shows A, R2 and R8 each show, Η or A, ^ R1 and R2 also show C together. -C e #alkyl R 3 shows 〇H, 0A or 〇A c, R4 shows hydrogen R3 and R4 also show a bond, r5 shows Ar or CH9ri-R,, 1 η ^ η. R9 in each case Shown q — C4 alkenyl or alkynyl, OH, OA, CHO, CO-A, CS-A, CGOH, COOA COO -alkyl-Ar, CS -OA, NO ?, NH ,, NHA, (please first «'Read the back of the page: > 2.Yi Shoushuo and then fill out the page). Install. • T. A. 4 (210X 297 public) 4 310) 98 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs Description of the invention (2) NA2, CN, F, C £, Br, I, CF3, SA, SO-A, or Ar. Ar shows a phenyl group which is unsubstituted or substituted once or twice by R1G. R6, r7 and The goods 〇 each show Η, A, HO, AO, CHO, ACO, CF CO, ACS, HOOC, AOOC, AO-CS, ACOO, 0 A-CS — O 'Jingji-yaki group, Weiji-yaki group, NO〗, NH〗, NHA, NA2, CN, F, C £, Br, I, CF3, AS, ASO, ASO2, AO-SO, AO-S〇2, AcNH, AO-CO-NH, H2 NSO, HANSO, A2 NSO, H2iNS〇2, HANS〇2, A2 NSO 2, H2 NCO, HANCO, A 2i \ CU, H2 NCS, HANCS, A2NCS, ASONH, AS 〇2 NH, AOSONH, A0S02 NH, ACO- Alkyl, nitro-alkyl, cyano-alkyl, A C (= N〇H), A-C (= NNH 2), H2P〇3 mA2P〇3, n shows 1, 2 or 3 A is not 〇〗 a Cg appearance _ alkyl shows ci-c6 alkylene Ac * C1-C8 alkanoyl or C7_C8 aroyl and their related classes. · The purpose of the present invention is to find a new compound with valuable value, especially the compound that can be used for the preparation of medicament. (Please read the back side first (Notes to fill out this page) A 4 (210X 2977 no) 5 A6 B6 Printed by the Ministry of Economic Affairs Standards Bureau V. Description of the invention (3) The inventor found that the compound of formula cI) and its physiologically acceptable compounds have a price The pharmacological properties (when it is tolerable), so they show a good use in the circulatory system, usually we can observe that when the amount is low, it can be used as a regular attack on the coronary system, and the high rate Under volume, see the fruit of lowering blood pressure. For example, when the effect on heart rate is kept low, the resistance that occurs in the coronary system decreases and the flow rate increases. In addition, this compound shows a relaxing effect on various smooth muscle groups of bismuth (gastrointestinal tract, respiratory system and uterus). The effect of such compounds can be measured by known methods, as shown below, for example, in EP-A 1 — 7 6 0 7 5, EP—Al — 1 7 3 8 4 8 or AU—A— 45547/85 C Derwent Farmdoc No. 8 6 0 8 1 7 6 9) and Arzneimi ttelforschung 25 (11), 1975, 1770-1776, proud of K. SM eesma η η et al. Examples of more suitable experimental animals are mice, years old, guinea pigs, dogs, cats, monkeys or pigs. This compound can therefore be used as an active ingredient in human drugs and silent drugs. They can also be used as intermediates for the preparation of active compounds of other drugs. A shown in the formula is preferably unbranched (: 丨 -C alkyl group, more preferably methyl, or J is (: 丨 -C4, especially C i, (: 2 or c 3, especially Suitable are Λ ethyl, propyl, isopropyl, butyl, isobutyl and secondary butyl, tertiary butyl, pentyl, isopentyl C 3 -methylbutyl), hexyl or isohexyl (4-Methylpentyl). If R1 and R2 are both shown as alkylene, the alkylene is preferably unbranched 4 (210Χ 297 Gong) 6 (Please read the notes on the back before filling in This page) • Installed. • Ordered • • Line • A6 B6 aioate 5. Description of the invention (4). Of, especially one (CH2) n—, where n shows 3, 4, 5 or 6ά “one alkyl” group The group is preferably one ch2—or one ch2 ch2—.

Ac is preferably _C6 C especially, C 2, C3 or acetylene) burnt acetyl group, especially suitable is methyl propyl group or ethyl group, but also can be propyl acetyl group, butyl acetyl group, isobutyl acetyl group, pentyl acetyl group or hexyl The acyl group can also be a benzoyl group, a meta- or para-toluene group, 1 or 2-naphthyl group. R1 and R2 are more suitable for each alkyl group, in particular, each is methyl or ethyl, preferably each is methyl and in addition R1 and R2 can both show a [CH2] 4- or a CCH. ) C-. 2 5 If R4 shows hydrogen, R3 is preferably 0H, or ϋ-CHO or o-coch3 °

Ar preferably represents unsubstituted phenyl. If Ar shows a substituted phenyl group (please read the precautions on the back before filling in this page). Printed by the Central Standards Bureau of the Ministry of Economic Affairs. The most substituted. The parameter η may be 1 or 2 alkenyl, preferably ethionyl and 1-propenyl or allyl. The more suitable definitions in R 6, R7 and R 4 are: A: methyl, also ethyl λ AO: methoxy •, or ethoxy 3 ACO: acetyl, or propylene Acyl group 3 ACS: thioethylammonium group »can also be thiopropyl acetyl group; AOOC: methoxycarbonyl 9 can also be ethoxym A4 (210X297 public splash) 7 210398 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economy ¾ '5. Description of the invention (5) AO-CS: ACOO: ACSO: hydroxyalkyl: Weiylalkyl: NHA: NA 2: A SO: as〇2: AO-SO: AO-S 〇2 · Ac-NH : Α Ο —CO — NH HANSO: a2 NSO: hans〇2: A 2 NSO 2: HANCO: a2 NOC: HANCS: methoxythiocarbonyl; also ethoxythiocarbonyl; ethoxy, or Propionyloxy; thioacetylacetoxy, or thiopropionyloxy; hydroxymethyl or 1 one or 2-hydroxyethyl; oxomethyl or 1-or 2-yuxyethyl; methylamino Ethylamino; dimethylamino or diethylamino; sulfenyl or ethanesulfinyl; sulfenyl or ethanesulfonyl; methoxysulfinyl or ethyl Oxysulfin Group; methoxysulfonyl or ethoxysulfonyl; acetamido or methylamino, propylamino or benzylamino; methoxycarbonylamino, or ethoxy Carbonylamino; methylamine sulfinyl or ethylamine sulfinyl; dimethylamine sulfinyl or diethylamine sulfinyl; methylamine sulfinyl or ethylamine sulfinyl; two Methanesulfonamide or diethylaminesulfonamide; N-methylaminoformamide or N-ethylaminoformamide; N, N-dimethylaminoformamide or N, N-diethylamine Carboxymethyl; N — Methyl-thiothiocarbamate or N — Ethylthiothiocarbamate; (Please read the precautions on the back before filling out this page) • Pack.. Order ·:- … Line. A 4 (210X 297 male)

ai〇3 «e V. Description of the invention (6) A2 ncs ASONH: as〇2 NH: AOSONH: AOSO〇NH or A6 B6 N, N-dimethyl mono-diethyl monothiodithiocarbamate; Methanesulfinylamino or ethanesulfinylamino; Methanesulfonyl or ethanesulfonylamino; Methoxysulfinylamino or ethoxysulfinylaminomethyl Oxasulfonylamino or ethoxysulfonylamino; ACO-alkenyl: 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl; methyl Nitronitroalkyl: nitroΛ, 1- or 2-nitroethyl; cyanoalkyl: cyanomethyl, 1- or 2-cyanoethyl; A—C (= NOH): I ~ month-deficient Ethyl or 1-month-deficient propyl; A- (k = NNH 0) α-hydrazinoethyl or 1 hydrazinopropyl; (please read the precautions on the back before filling this page) • Binding. R and R / groups are more suitable for the 6th and 7th positions of Seman system. However, they can also be in positions 5 and 6, 5 and 7, 5 and 8, 6 and 8 and 7 and 8. One of the R6 and R7 groups is more suitably H and the other is not H. The latter is more suitable for the 6th position, but it can also be in the 5th, 7th or 8th position, and is preferably CN or Ν〇2, also preferably CHO, ACOC especially acetyl), CF3 CO, AOOC ( Especially methoxycarbonyl or ethoxycarbonyl), AC〇〇 (especially acetyloxy) and F, C /, Br, I, CF3, h9nco, h9ncs wl nh9. . Line. Central Standard of the Ministry of Economic Affairs ¾. A 4 (210X297 public) 9 Α6 Β6 21〇δ · β V. Description of the invention (7) R8 group is more suitable for H and methyl or ethyl. {Please read the notes on the back before filling this page) R9 is more suitable for vinyl, ethynyl, ϋΗ, OA C especially methoxy or ethoxy), COOH, COOA C especially methoxycarbonyl or ethyl Oxylacryl), COOCH2C6H5, CN, or phenazine. Therefore, R5 is more suitable for phenyl, allyl, propargyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonyl Methyl, benzyloxylacrylmethyl, 2-aminoethyl, cyanomethyl, 2-cyanoethyl or benzyl. Therefore, the present invention is particularly concerned with compounds of formula I, wherein at least one of the groups has the meaning indicated above. In the following some of the more suitable groups of compounds can be represented by I a to I b, these are equivalent to formula I and wherein the group is not as detailed as indicated by formula I, but in la R1 and R2 show A; in Rb and R2 in I b show CH; 0 Rl and R2 in Ie show C3-C6 alkylene; R5 shows phenyl, allyl, propargyl, 2-ethyl in 2-d, 2- A0-ethyl, hydroxymethyl, AO-CO-CH 2, benzyloxycarbonylmethyl, 2-aminoethyl, cyanomethyl, 2-cyanoethyl or benzyl. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, R5 shows phenyl, allyl, propargyl, 2-hydroxyethyl, thiomethyl, methoxycarbonylmethyl, benzyloxycarbonylmethyl, 2-aminoethyl Group, cyanomethyl or benzyl; A 4 (210X297 public) 10

AB 2103S8 5. Description of the invention (8) In If R5 shows allyl; In Ig R1 and R2 each show CH 3 or both show a CCH 2) 4—or-(ch2) 5-; R5 shows phenyl, Allyl, propargyl, 2-hydroxyethyl, 2-A0-ethyl, carboxymethyl, A〇-CO-CH2, benzyloxycarbonylmethyl, 2-aminoethyl, cyanomethyl, 2_cyanoethyl or benzyl and R8 shows H or CH 3; in I h R 1 and R 2 each show hydrogen, R5 shows phenyl, allyl, propargyl, 2-hydroxyethyl, carboxymethyl Group, methoxycarbonylmethyl, benzyloxycarbonyl * methyl, 2-aminoethyl, cyanomethyl, benzyl and R8 shows H; in I i R1 and R2 each show CH3, R5 shows allyl And. R 8 shows Η ° In addition, the more suitable compounds are those represented by formula ′ and la ^ to i ^, these compounds are equivalent to those represented by formula I and la—Ii, but where incidentally R3 Compounds showing H, OH, OCHO or OCOCH3 and R4 showing H, especially those in which R3 shows OH and R4 shows H] and Ia to Ii. (Please read the precautions on the back before filling in this page)-Installation · Line · Printed by the Central Bureau of Standards of the Ministry of Economic Affairs

A 4 (210X297 Gong Li) U A6 B6 V. Description of the invention (9) In addition, the more suitable are the compounds of formula 1〃 and Ia〃 to Ii ", these are equivalent to formula I and 3 to 1 i, But the incidental r3 and R4 are combined into one bond. Furthermore, formulas 1, 1 ', 1々, a to Ii, Ia' to I i, and I a 〃 to I i 〃 are incidentally in each case Ca) R6 is not Η and R7 shows hydrogen; C b) R6 is not hydrogen and is located in the 6th position (please read the precautions on the back before filling in this page). Install · R7 shows hydrogen; (c) R6 shows NO, CN, CHO, ACO, HOOC , AOOC, F, C £, Bi-, I, CH3, H2NCO, H2NCS or nh2 and R7 shows hydrogen; Cd) R6 shows NO ?, CN, CHO, ACO, HOOC, AOOC, ACOO, F , c £, Br, I, CH3, h2 NCO, h2ncs or NH2 and located at the 6th position and set the line. Central Ministry of Economic Affairs printed by R7 shows H; C e) R6 shows N〇2, CN , Br or CH3〇OC and R 7 shows hydrogen; A 4 (210X297 public splash) 12 Ministry of Economic Affairs Central Standards Bureau printed dare 210338 V. Description of invention (10) 0 (f) R shows, CN, Br or CH 3〇OC Gu is at the 6th and 6th position and R 7 shows hydrogen; Cg) R6 shows NO? Or CN and R 7 shows hydrogen; ch) R6 shows No 2 or CN and is at the 6th position and R 7 shows hydrogen ; J .., C i) R6 shows CN and R7 shows hydrogen; C j) R6 shows CN and is located at the 6th position and R 7 shows hydrogen; in other aspects, the meanings of A, "alkyl" and Ac in the R1 to R8 groups above or below are indicated in formula I, unless otherwise specified. The present invention is further related to the preparation method of the chroman derivative of formula I according to item 1 of the patent scope, which is characterized by the chroman A 6 B6 of formula II (please read the precautions on the back before filling this page)- Outfit · Order · · · Fate · A 4 (210X297 public splash) 13 扪 〇3 Suppress — V. Description of the invention (11) R 6 A6 B6

Where eight χ _ γ represents a CH — CR8 or —CHE — CR3 R 8- and E represents CZ, Br, I, or the OH group functionalized by the reaction and R1, R2, R 3, R 6, R7 and R8 The meaning is pointed out in Formula I, and it reacts with the compound of formula]]] (please read the notes on the back before filling this page) 0

OH

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs where the meaning of r is indicated in formula i or reacts with a reactive derivative of a compound of formula m, or is characterized by a compound of formula jy, A 4 (210X297 Public Issue) 210338 V. Description of the invention (12) Ο

(Please read the precautions on the back before filling out this page) • Install · where R1, R2, R3, R4, R6, R7 and R8 are indicated in formula c I) or one of its anti-tendon derivatives and formula v The reaction of the compound

E-R5 V where the meanings of R5 and E are indicated in formula c 1) and formula C 2), respectively, or react with one of the reactive derivatives of the compound of formula V, and / or are characterized by • line · formula (1) Compound C wherein R3 represents OH and R4 represents H] is hydrogen removed and / or is characterized by one or more R3, R5, R6 and / or R7 groups in the compound of formula (1) being converted to other R3 , R5, the basic compound of R6 and / or R7 group printed by the Central Bureau of Standards of the Ministry of Economic Affairs and / or its characteristic in formula C1) is converted into one of its acid additions by acid treatment. Alternatively, the compound of formula C 1) is prepared from a known method, as described in the literature C for example in standard work such as Houben-Veyl, Kethoden der A 4 (210X297 mm) ις A 6 B6 210338 V. Description of the invention (13 ) organischen Chemie ^ Methods of organic chemistry jt (Please read the notes on the back before filling this page)

Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Viley & Sons, Inc., New York; and in the aforementioned patents), especially in known and suitable reaction conditions for this reaction. It may also use known mutation conditions, but it is not praised here. If necessary, the starting materials can be formed in situ, but they do not need to be separated from the reaction mixture but immediately reverse the tendon to generate the compound of formula (1). The compound of formula c 1) is preferably prepared by the reaction of the compound of formula β, and the compound of formula III, preferably in the presence of an inert stripping temperature between 0 and 150 °. / \ 8 The starting material of formula Π with X-Y = -CH-CR8-C 3, 4-epoxy color is more suitable. In principle, the starting materials Π and 11ί are known (for example, comparing German Offenlegungsschrift 3,726,261). 0 Although they are unknown, they can be prepared by known methods. Therefore, the starting material of formula Π C — X—Y — = Α8 -CH-CR8-) can be obtained by hydroxyacetophenone of formula 2-ho-r6r7c6h2-coch3 and R1 printed by the Central Bureau of Standards of the Ministry of Economic Affairs —CO— K2 reaction of ketones to produce 4-color full ketone methyl equivalent of formula Via 4 (210X297 public) 16 210338 A6 B6 5. Description of the invention (14) R6

X Ο YR a — X_ Y — = —CO—CH〗 一 " Vlb— X— Y — = —C〇 — (= CH—R “) _ YIc-xy- = -ch oh-chr8-Yld-X -· Y- = -CH = CR8-Λ Yje_X_Y- = -CHBr-CR 8OH-, 11 (please read the notes on the back before filling in this page) The Central Bureau of Economic Affairs of the Ministry of Economic Affairs is printed and then the appropriate formula R11—CHO Aldehydes CR11 = C, a CE alkyl 1 0) condensation to produce 3-alkylene-4-chromanone of formula ^ b, the ketone is then reduced with C such as NaBH4 to obtain chromanol of formula YI c , And then dehydrated with C (for example) p-toluenesulfonic acid to obtain chromene of formula W d and then oxidized with C (such as 3-chloroperbenzoic acid) to obtain the starting material. The subsequent oxidation can be carried out in eight steps. Therefore, It may be dissolved in an aqueous solution simultaneously with C, for example) N-bromosuccinimide, to first make bromoalcohol of formula YI e and finally remove HBr from the latter with a base, such as a sodium hydroxide solution. Formula VI d Chromene can also be prepared by the following reaction: Salicylaldehyde of formula 2-HO-R6R7-C 6H2-CHO is condensed with ketones of formula R Lc〇-CH2-R to produce formula 2-HO-R6R Η CH = CR 8 one CO-R 1 A 4 (210X297 splatter) 1 7 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. The ketone of the invention (15), then reacted with the organic compound of formula r2 — Li, and finally hydrolyzed to produce the formula 2-HO-r6r7c6H2-CH = Cr8 -C! ≪ 1 JR8 -0H diol and cyclization to remove water. In the compounds of formula Π (_X — Y— = 一 CHE — CR 3r 8 —) and v, especially suitable for “esterification by reaction "OH group" is an ester with an alkanesulfonic acid (where the alkyl group contains 1 to 6 carbons) or an aromatic sulfonic acid (where the aryl group contains 6 to 10 carbons). These compounds can be selected from the 4-color formula YIc Full alcohol or a compound of formula R5-OH is reacted with an inorganic acid halide such as PBr3, SOBrg " SOC ^ or / \ with sulfonyl chloride such as methane or p-toluene sulfonyl chloride. Suitable reaction derivation of JV The material is a suitable salt, such as Na or K salt, which can be prepared in situ. The inverse M of II and 1Π is best carried out in the presence of a base. Examples of suitable bases are the hydroxides of alkali metals or earth metals Compounds, carbonates, alcoholates, hydrides or amides, such as NaOH, KOH, Ca (OH) 2, Na 2C03 K2 C〇3, Na or K methanolate, B Terbutryn compound or alcoholate, NaH, KH, CaH2, NaNH2, KNH2, jian and organic hydrocarbons such as triethylamine or pyridine, it can then be used as a stand excess solvent from Jie Ji. Particularly suitable inert solvents are alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol; ethers such as diisopropyl ether, tetrahydrofuran or dioxane; glycol ethers such as ethylenedioxide Alcohol monomethyl or monoethyl ether C methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme) _ class such as propyl _ or butyronitrile class such as acetonitrile; nitrate such as nitromethane or nitrate Basic benzenes such as ethyl acetate; (please read the precautions on the back before filling in this page) • Order · • Line. A 4 (210X297 Public Issue) 18 A6 B6 八 210338 V. Invention description (i6) Brewed amines such as Dimethylformamide (DMF), dimethylacetamide or hexamethyltriamide phosphorous; sub-crushed species such as dimethylimine C DMSO); chlorinated hydrocarbons such as dichloromethane and chloroform , Trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. These shaved mixtures are also suitable

Mine I (X-Y = -CH-CRe-) can also be prepared in situ, for example, it can be obtained by the effect of emu on the related brominated alcohol Vi e. A particularly suitable procedure includes the use of an alcohol C (e.g. ethanol) as a solvent and the addition of an organic ember C (e.g. pyridine) with boiling for about 0.5 to 20 hours. The compound of formula I can also be prepared by the reaction of the compound of formula F and the compound of formula V, this reaction is preferably at a temperature between about 0 to about 1 50 ° C and the presence or absence of C) The inert solvent C (such as C) N-arylation or h ~ alkylation conditions, it also has advantages in the presence of the emu C (such as potassium carbonate). The preparation of the starting material of the formula is described in, for example, EP-A 〇2 7 3 2 6 2; it can also be easily obtained by C (for example) the compound of formula Π and the 3-hydroxyl group {please read the notes on the back side first Please fill in this page for details.) 6 Dihydro-6-pyridazine_ (, 6-pyridazinediol; formula m printed by the Central Standards Bureau of the Ministry of Economic Affairs, but η generation r5). The starting materials of formula v are known to be possible to replace the starting materials of formula IV or V with their reactive derivatives, such as related K or Na salt instead of IV, related alkyleneimines (aziridine, 2-methyl Alkyl aziridine) or phase alkylene oxide

Phenyl oxide) instead of the formula V [R CH 2-CH (NH2) -Cn_2H2n -4 A 4 (210X297 mm) 19 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of Invention (17) or -CH 2_CH 〇H—Cn_2 C2n_4] 2-amino or 2-hydroxy-1-E-ene; in the latter case, it is best to use high pressure c up to 100 bar) ° Compound C of formula 1 where R 3 represents OH and R 4 Hydrogen) can be converted into a compound C of formula 1 by a dehydration treatment (where R3 and R4 are both bonds), this conversion m is at a temperature between 0 and i50 ° C, and c is like DMSO in the solution.) Under the effect of alkali C such as NaH). . Dehydration can also be carried out in several steps, by * for example converting methanol I (R3 = OH, R 4 = H) into esters, such as sulfonate C such as camphorsulfonate) and the latter with a base C Such as NaOH). It is even possible to convert the R3, K5, Chi6 and / or Chi7 groups in the compound of Formula 1 to other R3, R5, R6 and / or R7 radicals. For example, H atoms can be replaced by halogen atoms by halogenation, or H can be replaced by nitrogen by nitration, and / or hydrolyzed esters can become carboxyl groups and / or a benzoyloxy carboxyl group can be hydrolyzed to become carboxyl groups (eg _ 中 的 Pd — C above) and / or esterify a carboxyl group and / or reduce the nitro group to an amine group and / or alkylate or aromatize an amine group or hydroxyl group and / or convert the cyano group C for example at 20-KKTC In water / methanol reacts with HC / to carboxyl group or transform (for example, in the presence of sodium phosphate in water / acetic acid / pyridine to interact with Raney nickel) to form benzoyl group or transform C for example in tert-butanol with KOH ) Thiocarbamyl)) nitrification is carried out under traditional conditions, for example at a temperature of 0 to 30 · <: (please read the precautions on the back before filling in this page). Install. ♦ Order · • Line · A4 (210X 297 issued) 20. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (18) Mixture with concentrated HNO3 and concentrated h2s〇4. , Halogenation can be carried out in a conventional inert stripping process at a temperature of 0 to 3 (TC, such as elemental chlorine or bromine.-Grade or secondary amine groups and / or 0H groups can be alkylated and cut It can be converted into related secondary or tertiary amine groups and / or alkoxy groups. Examples of suitable alkylation compounds are compounds of formula A-CZ, A-Br or A-I or related sulfuric acid or sulfonate esters such as Methyl chloride, bromine, iodide, dimethyl sulfate and methyl p-benzenesulfonate. It may also be possible, for example, to introduce one or dimethyl in formaldehyde in the presence of formic acid. Alkylation is best carried out in the presence of an inert solvent t: · C or not), its temperature is between about 0 to 120, the solvent is like DMF, the alkylation may also be in the catalyst (compared It is preferably carried out in the presence of a base, such as potassium tert-butyrate or NaH). Aromatic amines or hydroxyl groups are suitable for the aromatization of halides C (such as chloride or bromide) or Ac-OH carboxylic acid livers such as acetic acid, propyl chloride, isobutyl acetyl chloride, formic acid / acetic acid liver and Benzene chloride. It is also possible to add bases such as pyridine or triethylamine to this aromatization. Aromatization is best carried out in the presence or absence of an inert solvent, such as hydrocarbons such as toluene), or cyanides (such as ethyl cyanide) or amides (such as DMF) or excess quaternary Alkali (such as pyridine or triethylamine), and at a temperature of about 0 to 160 °, preferably 0 to 120 °. The formylation can be achieved by _ formic acid in the presence of pyridine, or using a mixture of formic acid and acetic acid. The base of formula 1 can be added with an acid to transform into acid addition bases. Acids that are particularly suitable for this reaction are those that can provide a physiologically acceptable base. Therefore, it may use inorganic acids such as sulfuric acid, nitric acid, S halogen acids such as hydrochloric acid or hydrobromine (please read the precautions on page 1 before filling out this page). Insects, • order · line · A 4 (210X297尨) 21 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (19) Acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, especially aliphatic, alicyclic > araliphatic, aromatic Or monocyclic or polycyclic carboxylic acid, sulfonic acid or sulfuric acid, such as formic acid, acetic acid, propionic acid, trimethyl acetic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid Acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, or Acetosulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- or disulfonic acid, dodecyl sulfuric acid. Those with physiologically unacceptable acids, such as bitter acid, can be used to purify compounds of formula 1. The compound of Formula 1 may have one or more centers (Chiral). Therefore, its preparation method can obtain racemic acid or optically active forms if optically active starting materials are used. If the compound has two or more pairs of palm centers, they can produce a racemic mixture in the synthesis, and the individual racemates from the mixture can be purified separately, for example, by recrystallization in inert stripping effect. Therefore, as in the compound C of formula 1, where R1 = R2, R3 represents OH and R4 represents H), it may have two seal palm centers; however, the reaction method of ϋ and i yields most of a racemic salt, which has The OH group in the third position is transferred to the fourth position of 1-R 5 -1,6-dihydro-6-oxo-pyridanyl-3-oxyl. If necessary, the obtained outer spinners can be dissolved in their enantiomers by mechanical, chemical or biochemically known methods. Therefore, the diastereomers can be colored from the racemate, which is the reaction of the optically active dissolution and cleavage with the racemate. Examples of proper dissolution of basic compounds of formula 1 are optically active acids such as D and L tartaric acid, diphenyl ether tartaric acid, and diethyl tartar (please read the precautions on the back before filling this page) A4 (210X297 Koji) 22 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy 5. Description of invention (20) Liquor, tansic acid, camphor sulfonic acid, mandelic acid, fruit acid or lactate 6 primary alcohols c I, R 3 = OH) can be paralyzed by using palmitic acid, such as isocyanate D — or L-α —toluoyl ester, and then dissolving C to compare EP — A 1 120,428). Different forms of diastereoisomers can be separated in a known manner, such as by subscribing to the role of embryos, and the sealed enantiomers of Formula I can be released from unsealed isomers in a known manner. The separation of the enantiomers can be further achieved by the chromatographic method on the optically active supporting substance. The compound of formula I and its physiologically acceptable compounds can be used for the preparation of medicines, chemical formulas, especially by non-chemical methods. It can be combined with at least one of solid, body and / or semi-liquid Formed or supplemented—prepared at the same time, if appropriate, it can be combined with other one or more plant active compounds to form a suitable medicament. The present invention also relates to the compound, especially the music formula, which contains at least one compound of formula I And / or a physiologically acceptable class. These formulations can be used as medicine or silent medicine for humans. Appropriate excipients are cut into organic or inorganic substances, which can be suitable for intestinal absorption of C (oral), Non-enterically absorbed or topical medicines that do not interact with new compounds such as water, vegetable oil, benzoyl alcohol, polyethylene glycol, triacetin, gelatin, carbohydrates such as lactose or starch, magnesium tartrate, talc, wool Fat, Vaseline reacted. Oral users are C in particular) tablets, troche tablets, bulging capsules, syrup, liquid medicine or drip medicine. For rectal use, drugs for parenteral absorption are more suitable for oils or aqueous solutions and suspensions, milk cuts or implants. Topical medications are ointments, creams, pastes, scrubs, gums, mists, foams, aerosols, ............................... ................................... Pretend ..................... ......... Order ................................ • Line (please first Read the precautions on the back and then fill out this page) A4 (210X297 public) 23 A 6 B6 210338 5. Description of the invention (21) {Please read the precautions on the back before filling out this page) Solution C is for example soluble in the following Solution: Alcohols such as ethanol or isoresorl, ethyl cyanide, DMF, dimethylacetamide, 1,2-propylene glycol or mixtures thereof and / or with water) or powder. The new compound can also be freeze-dried, and the resulting hydrophile can be used to prepare, for example, injection products. The liposome formula is also particularly suitable for local administration. The formulation may be sterilized and / or may contain supplementary shavings such as lubricating, anti-corrosive, stabilizing and / or moisturizing shavings, slow balancing substances, color shavings, flavoring medicines and / or fragrances. If necessary, they may also contain one or more other active compounds such as one or more vitamins. The compound of formula I and its physiologically acceptable compounds can be applied to human beings or ;, on animals, especially milk animals such as monkeys, dogs, cats, rats or old wind, and can be used in human or animal body sauce Treatment and suppression of diseases, especially the treatment and / or prevention of cardiovascular system insufficiency, especially the failure of cardiac compensator, chest embolism, irregular rhythm, irregularities in peripheral or cerebral blood vessels and morbidity related to hypertension, and Diseases associated with non-vascular muscle variations, such as asthma and bladder incontinence. Usually this requires the substance according to the invention to be taken in a manner similar to known anti-emetic or antihypertensive, such as nicanandil or cromakal im, preferably a cut amount of 0.01 to 5 mg, especially 0.02 To 0.5 mg / cut. The daily shaving amount is preferably 0.0001 to 0.1, especially 0.0003 to 0.01 mg / kg body weight. The specific volume of patients printed by the Central Bureau of Standards of each Ministry of Economy depends on the following different factors, such as the activity of the specific compound used, age, weight, health status, gender, hunger, time and route of administration, Exclude the speed, the combination of medicine and cutting, and the severity of the disease to be treated. Oral is a better way. A 4 (210X297 Koji) 210338 A6 _____ B6 V. Description of the invention (22) The compound of formula I and its compounds are further suitable for the treatment of cluster baldness, especially topical application. In particular, the use in this regard is those pharmaceutical formulations, which are suitable for the topical scalp management and as described above. They contain about 0.065 to 10 C, preferably 0.5 to 3%) by weight of at least one compound of formula I and / or at least one plant. Moreover, these compounds can be used to treat baldness, as described in WO 88/1) 0 8 2 2. In the following example, "as usual" means adding water if necessary, extracting with organic solvent (such as ethyl acetate), the organic phase is selected, dried with sodium sulfate, dehydrated and evaporated and colored Layer separation and / or crystallization purification ° u All temperatures in this context are ° C. Example 1 1 lg2,2-dimethyl-3,4-epoxy-6-cyanochrome C "fla"), 1.5 £ 3-hydroxy-1-phenyl-1,6-dihydropyridazine-1 The mixture of 6-ketone and 35 ml of ethanol was boiled for 14 hours, evaporated, and the retentate was analyzed by chromatography on silica gel to obtain 2,2-dimethyl-4 (1-phenyl-1,6- Dihydro-6-oxo one mouth squiry 3-oxyl) 6-cyano-3-chromanol C "A"), mp 203-206 ° ° Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (please first Read the precautions on the back and then fill out this page) The following 2,2-dimethyl-4-1- (1-phenyl-1,6-dihydro-6-oxo-mouth barrier 3-oxy) — 3 — Seman_ Prepared from related epoxides in a similar manner: A 4 (210X297 Gongai) 25 2i〇338 A 6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs · V. Description of the invention (23) 6 — Nitro 6-fluoro-6-chloro-6-bromo: 6-trifluoromethyl-6-methoxycarbonyl-6-ethoxycarbonyl-Example 2 2/2 / 2-dimethyl- 4- C 6 —Oxo-1,6-Dihydropyridyl A 3-oxo) -6-cyano-3-chromanol C "Fa"), 2 ml of allyl molybdenum :, a mixture of 3 g of potassium carbonate and 50 mi of acetone was cooked for 2 hours; here Then another 2 rn I of allyl bromide was added, and the mixture was cooked for another 2 hours. Evaporation and M are as above to obtain 2,2-dimethyl-4-C1-allyl-1,6-dihydro-6-oxo__throatyl-3-oxy) -6-cyano Base-3-chromanol, mp 1 4 5- 1 4 6 °. The following 2,2-dimethyl-6-cyano-3-chromanol is prepared in the same manner: 4- (1 -propynyl-1,6-dihydro-6-oxo-pyridazinyl One 3-. Oxygen) One, m. P. 1 8 5-1 8 6 °. 4 — [1 — (2 -methoxyethyl) -1,6-dihydro-6-oxo (please read the precautions on the back before filling in this page) A 4 (210X297 乂 没) 26

V. Description of the invention (24) Printed by the Central Standards Bureau of the Ministry of Drip ^ — Mouth-squeezing group 3-oxyl]-4 — [1— (2_ethoxyethyl) -1,6- 2-Li-6-oxygen Substituted-pyridazinyl-3-oxy] -4- (1 — (2-methylhexamethylene) -1,6-digas-6-oxo-pyridazinyl-3-oxy] -1; 4— [1 — (2 -ethylacetate) _1,6 -dihydrin-6 -oxo-zuxiaoji-3 -oxyj- f 4_ [1— (2thioethylacetate) -1 1,6-Di-L <6-6-Oxy "-pyridazinyl-3_oxy] -4 4- [1-carboxymethyl-1,6-diaza-6-oxo-pyridazinyl-1 3-oxo) one, πι · ρ · 212 — 216 ° 4 — (1—methoxymethoxymethyl-1, 6 — _qi-6 — oxo one mouth throat group 3-oxo) one, mp · 170-172 ° 4— (1—ethoxy-cut methyl-1,6 — — M — 6 —oxo one mouth voice. Yl-3-oxy) -4 — (1 benzyloxycarbonylmethyl-yl A 1,6-dihydro-6-oxo-pyridazinyl-3-oxy)-, mp 162-164. 4 one [1 one (2 -nitroethyl) _ 1,6--gas one 6-Oxygen one口 晓 基 一 3 —Oxygen] One- (please read Jfi on the back of the moraine first and then fill in this page) • Take a 4 (210X 297C no) 27 A6 B6 ftiosas V. Invention description (25) 4 — [ 1 — (2-dimethylaminoethyl) -1,6-dihydro, 6-oxo-pyridazinyl-3-oxy]-′ 4 — (1-aminomethyl-1,6 — — · Chloro-6-oxo-singyl-3-oxo)-, mp 201-203. Λ 4 — [1— (2-fluoroethyl) _1,6 —Dikryl-6 — ^ IN: — Azinyl-3-oxy] -4 4- [1-(2,2,2_trifluoroethyl) -1,6-dihydro-6-oxo-a xiaoxiao 3-oxy] -4 4- 〔1— (2_ methylthiomonoethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxy] -4 4 〔1 — (2-methylsulfinyl monoethyl )-1,6-dihydro_6 monooxo-pyridazinyl-3-oxy] -4 (1— 午 基 _1,6 — • hydrogen-6 —oxo-one-sucky radical-3 — Oxy) one, m.p. 1 9 7-1 9 9 0 The following 2,2,3-trimethyl-6-cyano-3-chromanol is also prepared in a similar manner: 4_ (1 one Allyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) -4- (1-propynyl-1,6-dihydro-6-oxo-pyridazinyl One 3-Oxygen) One A4 (210X297 Public Broadcasting) .......................................... ............ Pei ........................ Order …: ........................ • Please read the notes on the back before filling in the line t) The Central Bureau of Standards of the Ministry of Economic Affairs has printed 28 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (26) 4 1 [1-(2-methoxyethyl) _1, 6-2 m-gripping-oxomononutriazinyl 3-oxyl 〔4— 〔1 — (2 —ethoxyethyl) -1,6-dihydro-6-oxo-pyridazinyl-3 _oxy] -4 4 〔1 — (2 — methoxyethyl) )-1,6-di-Krypton-6-oxo-pyridazinyl-3-oxy] -4 4- [1 one (2-acetylethyl)-1,6-dihydro-6-oxo one Pyridazinyl-3-oxy]-"4 one [1-(2-thioethylacetate)-1,6-dihydro-6-oxo-pyridazinyl 3-oxy]-4_ 〔1-Complete methyl 1,6-Dihydro-6-oxo-a mouthful of a 3_oxy] -4_ [1 monomethoxycarbonylmethyl-1,6-dichloro-6-oxo-pyridazinyl 3- Oxygen]-4-[1 -ethoxycarbonylmethyl- 1,6-dihydro- 6-oxo-pyridoyl- 3_oxy_J-4 4 ((1-ping oxyoxomethyl) 1,6-dihydro-6-oxo-one xiaoji-3-oxy) -4 — [1 — (2-nitroethyl) -1,6-dihydro-6-oxo-1 (please first Read the precautions on the back and fill in this page) • Installed • • Ordered.. Line. A 4 (210Χ 297 public issue) 29 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (27) Zui Xiaoji 1 3 —Oxy) one. 4 — [1 one (2 -dimethylaminoethyl) one 1,6 ——gas_6 — oxo-pyridazinyl 3-oxyl J 4— (1-cyano Methyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) -4_ [1 — (2-cyanoethyl) -1,6-dim-6 -oxo-pyrida Azinyl-3-oxy] -4-([Ϊ 一 (2-fluoroethyl) -1,6-dikrypton-6-oxo one mouth Xiaoji-1 3 -Oxy] 4-[1-(2, 2, 2-trifluoroethyl)-1, 6-dihydro-6-oxo-pyridyl-3-oxy] 4-[1 — (2 · —methylthioethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxy] -4 4- [1 one (2-methylthiosulfinyl monoethyl ) A 1,6-dichloro-6-oxo-pyridazinyl-3-oxy] -4- (Γ- (2-methanesulfonyl-ethyl) -1,6-dihydro-6- Oxo-pyridazinyl-3-oxoyl-4-1 [1-subyl-1,6-nitrogen-6-oxo-1zuixiao-3-oxy) -1; the following 2,2 —Dimethyl-6 —Nitro-3 —chromanol: (Please read the precautions on the back before filling in this page) A4 (210X297 Public Issue) 30 210338 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economic Affairs DESCRIPTION OF THE INVENTION (28) 4-one (1-allylpropyl-1,6-dihydro-6-oxo-pyridazyl-3-oxy)-4— (1-propanyl-1,6-di Gas-6-oxo-pyridyl-3-oxy) _ 4 one [1 one (2-methoxyethyl)-1,6-dihydro-6- Substituted-pyridazinyl-3-oxy) -4 4- [1-(2 -ethoxyethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxy] -4 4- 〔1 — (2 — methyl ethyl) -1, 6_ dihydro-6 — oxo — mouth exposure group _ 3 — oxy] _ 4 1 [1 1 (2-ethyl acetyl) 1, 6-dihydro-6-oxo-pyridazinyl-3-oxy] -4 4- [1 — (2-thioethyl ethylthio) 1,6-dichloro-6- Azinyl-3-oxo] _ 4 one [1 -carboxymethyl-1,6_dihydro_6 -oxo-pyridazinyl 3-oxo] _ 4 one [1 monomethoxycarboxymethyl One 1,6-dihydro-6-oxo-pyridazinyl 3-oxy] _ 4 one [1—ethoxy quintomethyl-1,6 —di S-6 —oxo one mouth throat group 1 3 -Oxygen] One (please read the precautions on the back before filling in this page) • Install · • Line · A 4 (210X297 mm) 31 210338 A 6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Invention description (29 ) 4 -— (benzyloxycarboxymethyl-1,6-dihydro-6-oxo-monoazinyl-3-oxy] -4 4- [1 one (2- Ethyl) a 1,6-dihydro-6-oxo one right xiaoji a 3-oxyl J a 4 a [1 one (2-dimethylaminoethyl) a 1,6_dihydro-6 — Oxo-monoazinyl _ 3 -oxyl] _ 4— (1—cyanomethyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy] -4 4 [1 — (2-cyanoethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxy] -4-1- [1- (2-fluoroethyl) -1, dihydro-6- Oxo-pyridazinyl_3-oxy] -4- (1— (2,2,2-trifluoroethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxy Radical]-4-[1-(2-methylthio-ethyl)-1,6-dihydro- 6-oxo-pyridazinyl 3-oxy]-4-[1-(2-methyl Hexanoic acid-ethyl) -1,6-dihydro-6-oxo-pyridazinyl 3-oxo] _ 4— (1—benzyl-1,6-diS-6 —oxo-1 Pyridazinyl 3 t, please read the precautions on the back before filling out this page) • Ordered • • Green • A 4 (210X297 public splash) 32 210338 A6 B6 Printed by the Central Operations Bureau of the Ministry of Economic Affairs Description (30) Monooxy] 1. The following 2, 2-dimethyl-6-mo: 3-chromanol: 4- (1-allyl-1,6-dihydro-6-oxygen Substituted-pyridazinyl-3-oxy) -4_ (1 -propynyl-1,6-dihydro_6 -oxo-pyridazinyl-3-oxy)-4 — [1 — (2 — Methoxyethyl) -1,6-dihydro-6-oxo-exposed 3-oxy-1 4- [1- (2-ethoxyethyl) -1,6-dihydro-6- Oxygenated one-noise group 3-oxyl J-4 4- [1- (2-methylmethylethyl) -1,6-dihydro-6-oxo-pyridazinyl_3-oxy] -4 — [1 — (2 -ethyl ethyl)) 1,6-dihydro-6-oxo-pyridazinyl 3-oxygen ”_ 4 — [1 — (2 —thioethyl ethyl) ~ '1,6 —Chloro-6 —oxo-pyridyl- 3-oxo J — 4— (1—Compared with methyl-1,6-dihydro-6 —oxo-leptyl exposure _ 3 —Oxy) -4 (1—Methoxymethyl-1,6 ——Chloro-6-¾ generation one mouth (please read the precautions on the back before filling out this page). Line A 4 (210 X297 Gongchu) 33 210338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (31) Azinyl-3-oxy)-'4_ (1 monoethoxycarbonylmethyl-1,6--2 S-6 —Oxo-pyridanoyl-3-oxy) -4 (1-benzyloxycarbonylmethyl-1,6-dihydro_6-oxo-pyridoyl-3-oxy) -4 4- [ 1— (2-nitroethyl) —1,6-dihydro-p—oxo-monohydrazine-3—oxy J _ 4 — [1 — (2-dimethylaminoethyl λ-1, 6-dihydro-6-oxo-pyridazinyl-3-oxy] -4-1- (1 cyanomethyl-1,6-dihydro-6-oxo one mouth exposure 3-oxy) A 4-one [1-(2-fluoroethyl)-1,6-dihydro- 6 -oxo-pyridazinyl-3-oxy]-4-[1-(2, 2, 2-trifluoro Ethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxy] -4-1- (2-methylthiosulfonylethyl) -1,6-dihydro-6 — Oxo-pyridazinyl-3-oxyl J-4— [1— (2— methylpyridinylethyl) -1, 6 bis M-6 -6-oxo-1 Azinyl-3-oxy] -4— (1—noonyl-1,6-dihydro-6-oxo-1 cryothyl-3-oxyl) -1 (please read the precautions on the back before filling in this Page) • Installed • • Ordered •-Line • A 4 (210X297 male) 34 2i〇3 ^ 8 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (32) The following 2, 2-dimethyl one 6-Methoxyl-3-meranol: 4-((1-monopropylpropyl-1,6-di-M-6-oxo-pyridinyl-3_oxy) -1-4- (1-propyl Alkynyl-1,6'-digas-6-oxo-monoazinyl-3_oxy) -4-1- [1,2-methoxyethyl) -1,6-dihydro_6-oxo Azazinyl_ 3 -oxy] -5,> 々— [i — (2-ethoxyethyl) -1,6-dihydro-6-oxo_pyridazinyl-3-oxy] A 4- — [1 — (2-methylacetoethyl) a 1,6-dihydro-6-oxo-a mouth warming group 3-oxy] a 4-a [1 — (2- ethyl ugly ethyl) A 1,6 ——hydrogen 6 -oxo-pyridazinyl 3-oxy] a 4-[1-(2-(thioethyl ugly ethyl)-1, 6-dihydro one 6 Monooxo-pyridazinyl-3-oxo-4-one (1-carboxymethyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxo) -4 (1- Methoxyguanylmethyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) _ (Please read the precautions on the back before filling this page). ¾. • Thread 4 (210X297 Public Issue) 35 210330 Α6 Β6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs V. Description of the invention (33) 4 1- (1-ethoxycarbonylmethyl-1,6-dihydro-6-oxo-pyridazinyl-1 3-oxo) -4 (1-benzyloxycarbonylmethyl-1,6-dioxin-6-oxo-pyridazinyl-3-oxo) -4- (1— (2-nitroethyl ) A 1,6-dihydro-6-oxo-sorazine empty 3-oxo] -4 4- [1-(2-nitroethyl)-1,6-dihydro-6 -oxo one Azinyl monooxy] -4- (1 monochloromethyl-1,6-dihydro-6-oxo-oxathioyl-oxy J-4-4 [1-(2-cyanoethyl) -1 , 6-dihydro-6-oxo-pyridazinyl-oxy] -4 4- [1 — (2-fluoroethyl) -1,6-dihydro-6 —Oxo-pyridazinyl-oxy] -4— [1_ (2,2,2-difluoroethyl-1,6-diaza-6-oxo-pyridazinyl-oxy;)-4 — [1 · — (2 -methyl &amp; -ethyl) -1,6-dihydro-6-oxo-pyridazinyl-oxy-4 4-1 [1 — (2-methylthiosulfonyl-ethyl Radical) -1,6-dihydro-6-oxo-pyridazinyl-oxy ...................................... .......................... Pretend ...: '..................... ..... # ··.: .................... '' itch (please read the notes on the back before filling this page ) A4 (210X297 Gongchu) 36

6 6 AB Printed by the Central Equatorial Bureau of the Ministry of Economic Affairs V. Description of the invention (34) 4- [1 — (2-methylsulfonyl-ethyl) -1,6-dihydro-6 6 oxo_ίδι Exposure Monooxy] -4 — (1 —dry base 1,6_di M -6 —oxo-pyridazinyl monooxy)-and 2,2-butene-4 (1-pyridyl) 1,6 — 二 Μ—6—oxo one mouth throat—3—oxy) —6-cyano-3—chromanol and i J 2,2-pentane-1—4 (1-allyl-one 1,6-Dihydro-6-oxo-pyridazinyl-3-oxy) -6-cyano-3-chromanol. Example 3 A mixture of 1 g of Hana, 0.67 ml of aziridine and 10 ml of dioxane was heated in a sealed tube at 130 ° for 3 hours. After evaporation, the retentate was dissolved with dilute acid, and the solution was washed with dichloromethane to make it alkaline and proceed in the usual way. The resulting 2,2-dimethyl-4-1- [1- (2-aminoethyl) -1,6-dikryl-6-oxo-pyridanyl-3-oxy] _6-cyano-3 -The chromanol is recrystallized from ethyl cyanide / diethyl ether 1: 1. m. p. 1 6 7 — 1 6 9 °. The following 2,2-dimethyl-4- (1-mono (2-aminoethyl) -1,6-dihydro-6-oxo-pyridazinyl-3-oxyl-chromanol is similar The method is: (Please read the precautions on the back and then fill in this page) • Installed • • Ordered • • Line. A 4 (210X297 Gongji) 37 1 43! The Ministry of Economic Affairs of the Ministry of Economic Affairs printed foot 2 ^ 38 5 Description of the invention (35) 6-Nitro-6-fluoro-6-amino-6-bromo-6-tri «methyl-6-methoxycarbonyl-6-ethoxycarbonyl example 4 when 1 The Han &amp;, 1.6 Palace of ": 2 (:: 〇3 and 35 1111 of the _ mixture was heated with stirring for 8 hours into ethylene oxide. The mixture was stored overnight and after passing through, the furnace liquid was evaporated Obtained 2,2-dimethyl-4- (1- (2-ethyl))-1,6-diazo-6-oxo-a mouth exposure group 3-oxyl monochromanol, mP · 152— 154. The following 2,2-dimethyl-4 4- [1- (2-hydroxyethyl) -1,6-dihydro-6-oxo-throyl-3-oxy] -3 The chromanol is prepared in a similar manner: ^ δ —Nitro-6-fluoro-6-chloro 6 —Bromo-6 _Trifluoromethyl-6 —Methoxycarbonyl A6 B6 t Please read the note first, please fill in this page). Order * -coal. A4 (210Χ 297 Public) 38 2i〇338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (36) 6-Ethoxycarbonyl 1 'Example 5 8% lH 2g 2% NaH Add 2.82g 2nd, 2-dimethyl 4-bromo-6-cyano-3-color and 2.5 g of 3-hydroxy-1 1-phenyl-1,6-dihydro-6-pyridazine_ ^ 70ml DMS ϋ solution in a mixture of 20Χ: Stir for 3 days. Gradually obtained "Eight", 111 ·? · 203-206 ° ° Example 6 &lt; k 1 £ "厶 ', 1.5 苢 的 € ^-Zhang Yunyi〗 〇-sulfonyl chloride and 15 ml of pyridine mixture Stir at 90 ° C for 1.5 hours. Was evaporated, and the residue was dissolved in ethyl acetate, the organic phase was washed with dilute acid and water; dried over Na 2 S0 4 and evaporated again, and the resulting residue was dissolved It was purified in dichloromethane and purified by silica gel chromatography. 1.1 g of diastereomer of 4-camphorsulfonate was obtained and redissolved in 45 ml of methanol. 6 g of NaOH (E. Merck, Cat. Να 1 5 6 7) was added and proceeded in the usual way to obtain 2,2-dimethyl-1 4- (1 -phenyl-1,6-dihydro-6-oxo-pyridazinyl A 3-oxo) a 6 ~ cyano a 3-color is added with some "A" C removed by chromatographic separation) 〇 Example 7 Please read the precautions on the back before filling this page) • Install. • Order · Line · A 4 (210X297 Public Issue) 39 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 210338 A6 ___ B6 V. Description of the invention (37) 1 g of 2,2-dimethyl-4 — (1-benzyloxycarbonyl A —1,6 dihydro-6-oxo-pyridazinyl-3-oxy) -6-cyano-3-chromanol in 15 ml of methanol at 0.3g at 20 ° C and 1 bar 5% Pd — C is hydrogenated until it is terminated. The mixture is dewatered and evaporated, and then 2,2-dimethyl-4- (1-carboxymethyl-1,6-dihydro-6-oxo-pyridyl is obtained Azinyl-3-oxy) -6-cyano-3-chromanol »mp. 212-216 ° ° Buy Example 8: Ί 2g of" A ", 11.7ml of formic acid and 3.3ml of liver acetate mixture in 2 (TC is stored for 16 hours and then heated at 40-42 ° C for 2 hours. Evaporation and proceed in the usual way to obtain 2,2-dimethyl-3-methylformyloxy-4- (1-phenyl-1, 6-dihydro-6-oxo-pyridazinyl-3-oxy) -6-cyanochroman. The following is obtained in a similar manner using the corresponding 3-hydroxyl color: 2,2,3-trimethyl_ 3—Methoxyl 4-one (1-phenyl-1,6-dihydro-6-oxo-pyridazinyl) -6-cyanochroman 2,2-dimethyl-methyloxyl 4- (1-Pyropropyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy)- 6-cyano color full 0 2,2,3_trimethyl-3-methylformoxy-4 (1-allyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy Base) a 6-cyanide (please read the precautions on the back before filling out this page) • Install · _ line · A 4 (210X297 father not) 40 2 ^ 033® A 6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Invention Description (38) The primary color is full. ‘Example 9 A mixture of 1 g of“ A ”and 5 ml of acetic acid was boiled for one hour. Cool and proceed in the usual way, and then get 2,2-dimethyl-3_acetoxy-4- (1-phenyl-1-1,6-diM-6-oxo-pyridazinyl-3-oxy ) _ 6 —Cyan color is full. The following is obtained in a similar manner: 2,2,3-trimethyl-3-ethyldioxy-4- (1-monophenyl-1,6-difi-6-oxo-pyridazinyl-3-oxy ) A 6-cyano color full of 2,2-dimethyl-3-acetoxy-4- (1-allyl-1,6-dihydro-6-oxo-pyridyl-3-oxy) A 6-cyano color full 0 Example 10 2,2 of lg ——Methyl-4- (1-Phenyl-1,6-Dihydro-6-oxo-one xiaoxiaodi 3-oxy) -6 -Nitro-3 -chromanol 25〇1 丨 and 1 bar at 0.5% of £ 5? £ 1-&lt;: hydrogenation until termination. The mixture was leached and evaporated, and then 2,2_dimethyl-4- (1-phenyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) -6-amine was obtained Base 3-chromanol. (Please read the precautions on the back before filling in this page). Install. • Order • Line • A 4 (210X297 parent issue) 41 ai〇338 A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of invention (39) Following Obtained in a similar manner: '2,2,3-trimethyl-4- (1-phenyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) -6-amino A 3-chromanol. Example 11 lg of 2,2-dimethyl-4- (1-phenyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) -6 _Amino-3--chromanol in 15 m 1 HCOOH and 1 m 1 pyridine solution was boiled for 19 hours and evaporated. And proceed in the usual way to obtain 2,2_dimethyl-4- (1-phenyl_1,6-dihydro-6-oxo-oxaxiao-3-3-oxy) -6-carboxamide Base 3-chromanol. Example 12 1 g of 2,2-dimethyl-4- (1-phenyl-1,6-dihydro-6-oxomonoazinyl-3-oxy) -6-amino-3- The mixture of chromanol, 10 ml of ethanol and 10 ml of pyridine was kept at 20 ° C for 16 hours. It was evaporated and purified by layer analysis to obtain 2 5 2 — dimethyl-4 (1_phenyl-1 1,6-dihydro-6-oxo-pyridazinyl-3-oxy) -6-acetamide-3-chromanol. Example 13 (please read the precautions on the back before filling in this page) • Pei. • Ordered • • Line. A 4 (210X297 public splash) 42 2103¾8 A 6 B6 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of invention (40) HCZ was poured into a solution of 1 g of "A" in 50 ml of methanol and 2 ml of water for 14 hours. Cool down overnight. Precipitate 2,2_dimethylmethyl 4- (1-phenyl- 1,6-dihydro-6-oxo _ oxazinyl 3-oxy)-3-chromanol was filtered out. Example 14 3 g of "A", 31 g of Na3 P〇4. 12 H2 〇, 28 ml of batch pyridine, 28 ml of water, 67 ml of acetic acid and 25 g of Raney nickel (C water)) in Stir at 20 ° C for 3 hours. After passing through the water, proceed in the usual way to obtain 2,2-dimethyl-4- (1 -phenyl-1,6-dihydro-6-oxo-pyridazinyl-3-oxy) _6 -carboxamide Base one 3 full color alcohol, π · ρ · 256-257. . Example 15 3 g of "Α" was dissolved in 40 ml of t-butanol and Zunhuan Zun added 5.6 g of powdered KOH. Boil for 1 hour and proceed in the usual way to obtain 2,2-dimethyl-4- (1-phenyl-1,6-dihydro-6-oxo-azinyl-3-oxy) -6 Carbamate 3-chromanol ° Example 16 At 20 &quot; C, H2S is fed with 3 g of “A” in 20 ml of pyridine and 10 m 1 (please read the precautions on the back before filling out this page) • Install ’ • Order · Line. A 4 (210X297 public splash) 43 210338 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economy Λ, Invention Instructions (41) in the triethylamine mixed solution, after 5 hours, the compound was evaporated. Carry out in the usual way, and then get 2,2-dimethyl-4 (1-monophenyl-1,6-di-a-6-oxo-_throati-3-oxy) -6-thio-helium Formamide 3-chromanol. The following examples relate to pharmaceutical formulations containing compounds of formula I and / or their physiologically acceptable compounds. Example A ingot lg of 2,2-dimethyl-4- (1-pyropropyl-1,6-diaza-6-oxo-monoazinyl_3-oxy) -6-cyano-3 _ A mixture of chromanol, 4g of lactose, 1.2kg of potato starch, 0.2% of talc and 0.1kg of stearic acid is compressed into tablets in a conventional manner, so that each tablet obtained contains 0.1 mg Of the active compound. Example B The coated tablets are compressed like Tribute A and are coated in a conventional manner with clothing such as lactose, potato starch, talc, tragacanth and Example C capsules lkg-2, 2 , 3-trimethyl-4- (1-allyl-1,6-dihydro-6-oxo_py_yl_3-oxy) -6-cyano-3-chromanol for conventional use It is collected in hard gelatin so that each swelling gel contains 0.5 mg of active compound. A4 (210X 297g) (Please read the precautions on the back before filling this page)

A 6 B6 210338 5. Description of the invention (42) Example D Bottle 10g 2,2-dimethyl-4- (1-carboxymethyl-1,6-dihydro-6-oxo-pyridanyl-3-oxo Base) a 6-cyano-3-chromanol 70β 1,2-propanediol solution was added to the double-distilled water to 100β, sterile crazy, dispersed into the bottle and sealed aseptically. Each bottle contains 0.1 mg of active compound. Tablets, coated tablets, glue guns, bottles containing one or more other active compounds of formula I and / or their physiologically acceptable compounds can be prepared in a similar manner. (Please read the precautions on the back first and then fill out this page) Printed Armor 4 (210X297mm) 45

Claims (1)

A7 {Please flash pay the first note: &amp;# · &gt; /! # 蜞 k .71} T 4 (210X 2971: ^) 210338 10 η shows 1, 2 or 3 0 · 2. 2. 2, 2-2 Methyl-4 4-C.1 monohoofyl-1,6-digas ..-...- 6-daidai-1_ 晓 基 一 3 monooxy) 一 6 — 银 鉴 一 3 One-color full alcohol 0 k 3. A method for preparing the color full-blown: raw + ... Where X-Y represents a CH E represents C /, Br CR 8 _ or _CHE — CRd R8 — once I or an OH group which has been reversely esterified, and —R 1, R2, R3, R6, ruler 7 and ruler 8 are defined as follows? As shown, go against the compound of formula I or its sodium and potassium salt "quot; Ο R ΙΠ ΟΗ 30 • wherein R5 is defined as shown in formula I, or its special feature lies in the compound of formula Han, sodium citrate or potassium salt 1 R wherein R1, R2, R3, R4, R6, r7 and R8 are defined as shown in formula I, and the compound of formula V is E-R'Y where R5 and E are defined as formula I and formula respectively I shown, or react with one of the following compounds .; Η Η \ c / 5 and / or the compound of formula I characterized by R showing COOA is converted to R • 1 · the compound of formula I showing COOH and / or its characteristic is-acid treatment: the compound of formula I is converted to Sour Fen I becomes a pie. 4.-The medical group for the treatment or prevention of angina, high blood mollusc Qi: a substance, which is characterized by containing at least one compound of formula 12: and / or one that is physiologically acceptable Z-class. Ti (310X307) 3 No. 79104390 Patent Application Chinese Supplementary Pharmacology Experiment Report Amendment Page Revised in November 1981, Wei page / Xing Zhongxiong np rc] R5: Blood pressure reduction D [ipm. Hg] Selchi 2J IC50- 庤 溱 S 〔 m0l / l〕 Highly polarized 3 :) 'Cmo 1/1 3; mv 27/10 212-216 -ch2cooh -15 2 x ίο-5 10-4 20 28/13. 丄 97-199 -CH2-pheny1 -48 3 x 10-5 10-4 6 26/13 145-146 -ch2-ch = ch2 · -106 2 x ΙΟ &quot; 7 10-β 31 27/12 170-172 -CH2-COOCH3 -24 4 x 10 -5 ίο— 24 27/16 162-164 -CHiCOO-benzy1 -13 &gt; l〇-s ίο-5 4 28/3 37/14 201-203 167-169 -CH2-CH, -CH2-CH2NH2 -5i 2 χ ΙΟ-6 &gt; ΙΟ-4 丄 〇-6 丄 0-4 22 9 26/19 185-186 -ch2-c = ch -74 6 χ ΙΟ'7 ίο-4 22 38/11 152-154- CH2-CH20H -15 3 χ ΙΟ-6 10-S 32 conducted different tests according to the method listed in this case. (Page 6/8-14 lines; Chinese version) 1) Blood pressure lowering activity (SHR, orally administered to rats) Dosage unit: lmg per kg body weight 2) Relaxing effect: inhibition of contraction of isolated blood vessels caused by motility muscles (Porcine Coronary Artery) 3) High polarization effect test on isolated rabbit pulmonary artery; mV: relative membrane potential change